Systemic sclerosis (SSc; scleroderma) is a complicated autoimmune disease characterized by blood vessel change (vasculopathy) and scarring (fibrosis). SSc is a disease in which the blood vessel changes precede fibrosis. Most importantly, early diagnosis may result in improved outcomes for SSc patients. Our pilot data using flow-mediated dilation (FMD), a noninvasive, objectively measured parameter, suggests that compared to healthy controls, SSc patients had significantly smaller brachial artery diameter, and blunted peripheral vascular reactivity and endothelial function. SSc patients with digital ulcers (DU) have even greater impairments in endothelial function compared to those without DU. FMD testing potentially has clinical utility to identify SSc patients at risk for DU an may be a promising biomarker of SSc-vasculopathy longitudinal studies. FMD may be used to describe pathogenic processes or pharmacologic response to SSc therapeutics. As such, this project will establish a solid initial base of skills and experiences that will not only develop Dr Frech as an independent clinician scientist, but will result in a careful characterization of the vasculopathy in patients with SSc through a collaborative approach and provide an endothelial targeted clinical intervention when it may have the largest potential to impact outcomes. In the first specific aim, the impact of vasculopathy on SSc patients will be assessed through patient-related and reported outcomes (PRO) and FMD testing will be performed at baseline and at 6 month intervals during clinic visits. The predictive value of FMD for the development of SSc complications (end-stage vasculopathies) will be determined. In patients who consent to skin biopsy, systemic, cellular and molecular events such as circulating and skin arteriole ROS-derived radical species, circulating and skin arteriolar markers of oxidant damage, skin arteriole expression of the oxidant enzyme NADPH oxidase and circulating antioxidants and skin arteriole expression of antioxidant enzymes will be assessed. In the second specific aim, vascular function will be assessed by measuring FMD and reactive hyperemia in patients with SSc with and without complications (i.e. end-stage vasculopathy) in the absence or presence of oral BH4 treatment for 5 days using a randomized cross-over double-blind design. In patients who consent to skin biopsy correlation analysis of oxidative stress markers will be assessed in patients with SSc with and without complications in the absence or presence of oral BH4 treatment using a randomized cross-over, double-blind design. In summary, the proposed studies will adopt an integrative approach to better define the pathophysiology of vasculopathy in SSc. We will validate a novel, non-invasive technique to evaluate vasculopathy in SSc. Additionally, we will examine if BH4, a FDA-approved drug, is effective in ameliorating vascular dysfunction in patients with SSc. Finally, to provide further mechanistic insight, we will explore the link between oxidative stress and the vascular endothelial dysfunction in SSc. If successful, these aims have the potential to improve clinical outcomes in SSc.